Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. Interpretation: In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR–/ALK– NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. Funding: AstraZeneca.
Bibliographical noteFunding Information:
The results of the ATLANTIC study show that the anti-PD-L1 monoclonal antibody durvalumab has clinical activity and an acceptable tolerability profile in heavily pretreated patients with advanced NSCLC. Durable responses and encouraging overall survival data were observed across cohorts of patients with NSCLC defined by EGFR and ALK status and tumour PD-L1 expression. Our findings confirm preliminary results from a previous phase 1–2 study of durvalumab in patients with advanced NSCLC, 17 and show that the clinical activity and safety profile of durvalumab is consistent with other anti-PD-1 and anti-PD-L1 agents. We report the final analysis of the primary efficacy endpoint, the proportion of patients who achieved an objective response. Responses were recorded across the three cohorts, and the proportions of patients who achieved a response were generally lower in patients with EGFR +/ ALK + NSCLC than in those with EGFR −/ ALK − NSCLC. Higher PD-L1 expression enriched for response both in patients with EGFR +/ ALK + NSCLC (cohort 1) and those with EGFR −/ ALK − NSCLC (cohort 2). The highest proportion of patients achieving an objective response (31%) was in cohort 3 ( EGFR −/ ALK −, ≥90% of tumour cells expressing PD-L1), although the proportion with an objective response in a subset of patients in cohort 2 with at least 90% of tumour cells expressing PD-L1 was lower (16%). Thus, the higher proportion of patients who achieved an objective response in cohort 3 might be due to a factor other than the increased PD-L1 expression; for example, patients in cohort 3 were less heavily pretreated than those in cohort 2. Good durability of response was seen across responders in all cohorts, irrespective of PD-L1 expression; however, duration of follow-up was not consistent between the cohorts. In the cohort 2 subpopulation with at least 25% of tumour cells expressing PD-L1, the proportions of patients achieving an objective response were similar in all subgroups by baseline characteristics, including squamous and non-squamous histologies, current or former smokers and those who had never smoked, and CNS metastases (present and absent). Irrespective of EGFR or ALK status, median overall survival was higher in patients with at least 25% of tumour cells expressing PD-L1 (approximately 11–13 months), although the values in patients with less than 25% of tumour cells expressing PD-L1 (approximately 9–10 months) still remain encouraging. At data cutoff, median overall survival had not been reached in cohort 3, although the overall survival at 1 year was favourable at 51%. The ATLANTIC data reflect the durvalumab clinical activity observed in a phase 1–2 study 17 in patients with advanced NSCLC: the proportion of patients who achieved an objective response was 17·5% in the overall population (n=285), and 13·0% in the third-line and later treatment setting (n=146). Similar to ATLANTIC, the proportion of patients with at least 25% of tumour cells expressing PD-L1 who achieved an objective response was higher, and their overall survival was longer, than patients with less than 25% of tumour cells expressing PD-L1 (in patients treated with third-line and later durvalumab, 22·0% vs 6·1% achieved an objective response, and median overall survival was 13·0 vs 7·6 months). 17 Although several immune checkpoint inhibitor trials have included patients with advanced NSCLC who have received at least two previous lines of therapy, few have focused only on the third-line and later setting, and none have prospectively analysed EGFR -driven or ALK -driven tumours. In CheckMate 063, 22 a phase 2, single-arm trial of third-line and later nivolumab in advanced squamous NSCLC, the proportion of patients who achieved an objective response was 14·5% in the overall population and 24% in patients with at least 5% of tumour cells with PD-L1 expression; median progression-free survival was 1·9 months (95% CI 1·8–3·2) and median overall survival was 8·2 months (6·1–10·9) in the overall population. In patients with previously treated advanced NSCLC who received pembrolizumab in the uncontrolled KEYNOTE 001 trial, the proportion of patients who achieved an objective response was 18%, median progression-free survival was 3·0 months (2·2–4·0), and median overall survival was 9·3 months (8·4–12·4). 23 These activities seem generally comparable with that of durvalumab in the treatment of patients with EGFR −/ ALK − NSCLC in ATLANTIC. The inclusion of an independent cohort of patients with EGFR +/ ALK + NSCLC in ATLANTIC permitted prospective assessment of an immune checkpoint inhibitor in a population who have a distinct clinical course and prognosis compared with EGFR −/ ALK − patients. 24 Retrospective analyses in patients with advanced NSCLC have shown no survival benefit of anti-PD-1 or anti-PD-L1 over docetaxel in EGFR + subgroups (overall survival hazard ratios vs docetaxel: nivolumab 1·18, 95% CI 0·69–2·00; 25 pembrolizumab 0·88, 0·45–1·70; 26 atezolizumab 1·24, 0·71–2·18 27 and 0·99, 0·29–3·40). 28 A meta-analysis 29 of three of these studies 25,26,28 showed that the immune checkpoint inhibitors significantly prolonged overall survival compared with docetaxel in the overall population and EGFR− subgroup, but not in the EGFR + subgroup. The preliminary antitumour activity and overall survival data observed in the present study with durvalumab in heavily pretreated patients with EGFR+ NSCLC (including previous EGFR tyrosine kinase inhibitor therapy) with at least 25% of tumour cells with PD-L1 expression seem encouraging on the basis of historical comparisons with studies in patients with pretreated, predominantly EGFR− NSCLC. 22,23,25–28 The proportion of patients with at least 25% of tumour cells expressing PD-L1 who achieved an objective response in cohort 1 ( EGFR +/ ALK +) was not substantially lower than that in cohort 2 ( EGFR −/ ALK −; 12·2% vs 16·4%) and the difference in the proportion of patients achieving a response was even smaller when focusing on the EGFR + subpopulation (proportion of EGFR + patients in cohort 1 who achieved an objective response 14·1%; appendix p 16 ). However, patients with EGFR + NSCLC with PD-L1 expression in at least 25% of cells are a small subset (approximately 26% of patients with EGFR +/ ALK + NSCLC and 24% of patients with EGFR + NSCLC in this study; appendix p 12 ). The small number of patients with ALK + NSCLC leaves the role of immune checkpoint inhibitors unresolved in this subpopulation. Both ALK + and EGFR + lung cancer, which mostly occur in patients who have never smoked, have been shown to have low mutational burden. 30 This low burden might explain the reduced activity of immune checkpoint inhibitors in patients with EGFR + NSCLC, compared with patients with EGFR− NSCLC, observed consistently across studies. 29 So far, little is known about the responsiveness of ALK + NSCLC to immune checkpoint inhibitors. With no comparator arm, the uncontrolled nature of data from the ATLANTIC study is subject to patient selection; thus, further study in both EGFR + and ALK + subpopulations is warranted. Furthermore, because the duration of follow-up varied across the cohorts, subsequent analyses of the data from this study will be needed to determine whether the duration of responses is similar between patients with EGFR +/ ALK + NSCLC and those with EGFR −/ ALK − NSCLC. Future analyses could also include evaluation of whether durvalumab activity in the EGFR +/ ALK + population is related to increased tumour mutational burden after multiple disease progressions, and whether patients with EGFR + NSCLC progressed because of the onset of EGFR Thr790Met mutation. Durvalumab monotherapy had an acceptable tolerability profile in the ATLANTIC study: most adverse events were low grade, and immune-mediated adverse events were manageable with standard treatment guidelines. The percentage of patients who discontinued durvalumab because of treatment-related adverse events was low across all three cohorts. Cohort 3 had higher incidences of treatment-related grade 3 or 4 adverse events, serious adverse events, adverse events of special interest, and immune-mediated adverse events than cohorts 1 and 2, which might be explained by the longer duration of treatment exposure in cohort 3. In cohort 1, previous treatment with at least one tyrosine kinase inhibitor was a study inclusion criterion; however, the proportion of patients who had a treatment-related adverse event of special interest of pneumonitis was lower in cohort 1 than in cohorts 2 and 3. In cohort 1, 98% of patients did not experience pneumonitis, which suggests there is no increased risk of pneumonitis in patients treated with durvalumab following previous tyrosine kinase inhibitors at some point in their treatment history. The safety profile of durvalumab in ATLANTIC was consistent with other anti-PD-1 and anti-PD-L1 monoclonal antibodies in previously treated patients with advanced NSCLC. 25–27 Limitations of our study include the absence of a comparator arm and the short duration of follow-up, particularly in cohorts 1 and 3. Comparison between the cohorts was not an objective of the study; thus, no formal statistical comparison was done. The three cohorts were independent and enrolled in different timeframes. Between-cohort differences in treatment exposure (cohort 1 had the shortest duration and cohort 3 had the longest duration) and demographic and disease characteristics (in general, the characteristics of cohorts 2 and 3 were similar and representative of an EGFR −/ ALK − population, whereas cohort 1 showed differences consistent with their EGFR +/ ALK + status) further preclude any informal comparison of efficacy or safety results. The inclusion criterion of WHO performance status score of 0 or 1 is a good performance status for such heavily pretreated patients; therefore, the trial population might not be truly representative of real-world patients. However, at the time that ATLANTIC was initiated, the safety profile of durvalumab in patients with NSCLC after at least two previous therapies was unknown. The performance status restriction was a means to ensure patients were fit enough to tolerate unanticipated toxicities, and is in keeping with trials that included patients in the third-line and later treatment setting. 22,23,27,28 The ATLANTIC study makes an important contribution to the body of evidence on the efficacy of immune checkpoint inhibitors in NSCLC. Our results show that durvalumab has clinical activity in patients with NSCLC who are heavily pretreated; the proportion of patients achieving a response were higher in patients whose tumours expressed higher levels of PD-L1, but responses were durable irrespective of PD-L1 expression status. Although clinical applications of these data might be few, one potentially interesting question is whether durvalumab has a role in the treatment of EGFR + tumours with high PD-L1 expression, and could be the subject of further clinical investigation. For study protocol see https://astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=2257 Contributors MCG, B-CC, JM, JV, JCJ, CC, KP, RAS, and PAD collected, analysed, and interpreted the data. J-HK, HL, and JEG collected and interpreted the data. JP, PB, and PW-P collected the data. YH analysed the data. CW and NAR analysed and interpreted the data. JEG, CW, PAD, and NAR contributed to the study design. JM undertook literature searches. All authors drafted the manuscript and approved the final draft. Declaration of interests MCG received personal fees for advisory board participation from AstraZeneca, Roche, Bristol-Myers Squibb, and Merck Sharp and Dohme during this study. JV received an institutional research grant from AstraZeneca and served AstraZeneca in an advisory capacity during this study. HL received personal fees from AstraZeneca, Roche, Merck Sharp and Dohme, Bristol-Myers Squibb, Pfizer, Novartis, Lilly, and Amgen, and non-financial support from AstraZeneca, Roche, Merck Sharp and Dohme, Bristol-Myers Squibb, Pfizer, Lilly, and Amgen, all outside the submitted work. JEG received a research fund grant from AstraZeneca and personal fees for advisory services, outside the submitted work. JP received clinical trial funding from AstraZeneca during this study; received clinical trial funding from Genentech, Bristol-Myers Squibb, Curis, Corvus, EMD Serono, and Macrogenics outside the submitted work; reports DSMC and speakers' bureau participation with Bristol-Myers Squibb outside the submitted work; reports speakers' bureau participation with Genentech and Merck outside the submitted work; has a patent T-cell immunotherapy development pending; is a founder and owner of BioCytics, which is a clinical research laboratory developing T-cell immunotherapy; and has previously bought stock in the T-cell companies LionBiotech, Juno, Blue Bird, Kite Pharma, and ZioPharm. CC has received fees during the past 5 years for attending scientific meetings, speaking, organising research, and providing consulting services from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi-Aventis, Lilly, Novartis, Merck Sharp and Dohme, Bristol-Myers Squibb, and Amgen, outside the submitted work. PB participated in advisory boards for Eli Lilly, Bristol-Myers Squibb, and Boehringer Ingelheim, outside the submitted work. PW-P received personal fees for advisory board participation from AstraZeneca, Merck, Bristol-Myers Squibb, and Lilly, outside the submitted work. RAS received a research grant from AstraZeneca and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Lilly, Pfizer, Roche, Taiho, and Bristol-Myers Squibb, outside the submitted work. YH, CW, and PAD are employees of AstraZeneca and hold shares in AstraZeneca. NAR received personal fees from Merck, Bristol-Myers Squibb, Roche, Novartis, Pfizer, and Lilly, outside the submitted work. All other authors declare no competing interests. Acknowledgments We thank the patients, their families, and their caregivers for participating in the ATLANTIC study, and all investigators and site personnel. We thank Marc Ballas, formerly of AstraZeneca, for his contribution to the study. This study was sponsored by AstraZeneca. Medical writing and editorial assistance were provided by Samantha Holmes, of Cirrus Communications, an Ashfield Company (Macclesfield, UK), and was funded by AstraZeneca.
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